The central theme of the program project is to delineate the molecular mechanisms involved in the regulation of cell growth. Towards that goal we have proposed seven project. 1: Molecular Analysis of LFG. Studies are designed to understand the molecular and biochemical function of LFG, an anti-apoptotic gene which prevents Fas induced cell death. 2. Nuclear signaling pathways regulated by phosphorylation and ubiquitination. Experiments are proposed to understand the mechanism of RING finger associated ubiquitin ligases (E3) activity associated with down regulation of activated receptor protein-tyrosine kinases and tumor suppressor gene, BRCA1. 3: Control of cellular proliferation by the cAMP responsive factor CREB. Studies are designed to test that CREB induces proliferation of developing chondrocytes in response to cAMP activation, by stimulating expression of cell cycle regulatory genes. 4: Mechanism of LEF-1: Beta-catenin trans-activation. Studies are designed to characterize the mechanism of transcriptional activation by LEF-1: Beta-catenin signaling complex using in vitro transcription system with both non-chromatin templates. 5: Mechanisms of transcriptional regulation by p53 on suppressor protein p53 function as a transcription activator using natural target promoter, p21. 6: Oncogenic activation of nuclear receptors. The major focus of this project will be to focus on biochemical, molecular, and cellular aspects of acute pro-myelocytic leukemia (APL), particularly as it relates to oncogenic activation of the PML-RAR fusion protein. 7: Structural analysis of cell growth regulators. The goal of this project is to use protein x-ray crystallography to uncover the stereochemical principles underlying signal transducers capable of phosphorylation and ubiquitination of proteins. In addition we have also proposed three core facilities. Core Protein Facility. This core will support synthesis of peptides, raise antisera, microsequence proteins, and analyze protein modifications. Core: DNA microarray. This is designed to catalogue gene expression from a variety of normal and abnormal cells and tissues using recently developed "microarray" technology. Core: Administrative, will provide the administrative assistance to the program project. There is an extensive synergy and interdependence among various projects and cores to allow fruitful collaboration to delineate the complex molecular events leading to uncontrolled growth of a cell.